Investigations are proposed into the neuropharmacological properties and biodisposition of the optical isomers (enantiomorphs) of the anesthetic, ketamine, a member of the aryl cyclohexylamine class of psychotropic drugs. Our ongoing assessment of CNS actions of the two compounds will be continued including study of analgesic, hypnotic, and central stimulatory effects. Known metabolities of the two enantiomorphs will be synthesized and examined for their neuropharmacological effects in laboratory animals including the mouse and rat. The overall biodisposition of individual optical isomers (and their racemic) mixture will be examined in these laboratory animals and in humans. Attempts will be made to correlate pharmacologic actions with data on metabolism and on biodisposition of the ketamine isomers to determine if specific effects relate to formation of active metabolities. Techniques of analysis will involve capillary GC, HPLC and mass spectrometric methods. Novel metabolities will be isolated from biological tissues (e.g. plasma of whole animals or hepatic incubates), identified and synthesized for study of individual properties. Attempts will be made to synthesize a cyclohexylamine congener of phencyclidine and/or ketamine capable of irreversible interactions with specific brain binding sites for this class of molecule. Major scientific disciplines involved are pharmacology and chemistry. The long-term objectives are to elucidate the mechanisms underlying the CNS effects of arylcyclohexylamines as part of a fundamental approach to understanding both useful anesthetic/analgesic actions and adverse neurotoxic actions.